ABSTRACT: The overarching goal of this R01 application from a collaborative new and early stage investigator, is to define the mechanistic basis for recurrent functional mitral regurgitation (FMR) after undersizing mitral annuloplasty(UMA) in heart failure patients, and translate the mechanistic insights into the development of a new surgical technique that eliminates this problem. 2-3 million Americans suffer from FMR developing from ischemic cardiomyopathy. Volume overload imposed by FMR not only elevates pulmonary pressures and causes dyspnea, but imposes a unique low pressure hemodynamic stress on the already cardiomyopathic ventricle. This stress elevates sympathetic drive and causes breakdown of cardiac extracellular matrix and leads to rapid ventricular dysfunction. Timely repair of FMR is now considered necessary and patients are promptly referred for surgical repair, but poor repair durability and post-repair recurrence of FMR continue to haunt these patients and their cardiologists. A recent randomized controlled trial reported that in patients receiving FMR repair with an undersizing annuloplasty ring (current gold standard), FMR was fully repaired at the time of surgery, but at 1 year 34% of the patients developed recurrent moderate or greater FMR, and at 2 years 64% had repair failure. This situation needs to be improved, but mechanistic insights into recurrent FMR after annuloplasty are scarce and thus techniques for improvement are lacking. We developed and validated a novel patient imaging (3D echo+MRI) derived biomechanical modeling platform to investigate the mechanism causing recurrent FMR in patients receiving annuloplasty. A retrospective study was performed using this model on a select set of FMR patient images at our institution, which resulted in a hypothesis that poor inter- papillary muscle lateral shortening governs the risk of developing FMR, and that surgically approximating the papillary muscles can eliminate recurrent FMR. We validated our hypothesis in an ex-vivo mitral valve model and in a chronic swine model, and recently published these results. In this R01 application, we propose to conduct a prospective trial to confirm that patients with poor inter-papillary muscle lateral shortening develop recurrent FMR after mitral annuloplasty (Aim 1); that poor-inter papillary muscle lateral shortening leads to elevated tethering forces on the anterior and posterior mitral leaflet edges that reduces their systolic parallelization that is essential to achieve adequate coaptation (Aim 2); and finally propose papillary muscle approximation as a new technique to reduce recurrent FMR after annuloplasty, and enable reverse ventricular remodeling(Aim 3). A multi-disciplinary team has been assembled with expertise in heart valve biomechanics, cardiac surgery, cardiac imaging and clinical trials, in a high volume cardiac surgery center that provides an excellent environment to conduct this work. Ultimately, this work would provide unprecedented mechanistic insights into recurrent FMR after annuloplasty, and validate the use of a new technique to address this problem. The translational potential of this work is high and these patients will benefit from the outcomes.